Mammalian cell membranes perform very important functions relating to the structural integrity and activity of various cells and tissues. Of particular interest in membrane physiology is the study of trans-membrane ion channels which act to directly control a variety of physiological, pharmacological and cellular processes. Numerous ion channels have been identified including calcium (Ca), sodium (Na) and potassium (K) channels, each of which have been analyzed in detail to determine their roles in physiological processes in vertebrate and insect cells.
A great deal of attention has been focused on potassium channels because of their involvement in maintaining normal cellular homeostasis. A number of these potassium channels open in response to changes in the cell membrane potential. Many voltage-gated potassium channels have been identified and are distinguishable based on their electrophysiological and pharmacological properties. Potassium currents have been shown to be more diverse than sodium or calcium currents and also play a role in determining the way a cell responds to an external stimulus. The diversity of potassium channels and their important physiological role highlights their potential as targets for developing therapeutic agents for various diseases.
Inhibitors of potassium channels lead to a decrease in potassium ion movement across cell membranes. Consequently, such inhibitors induce prolongation of the electrical action potential or membrane potential depolarization in cells containing the inhibited or blocked potassium channels. Prolonging of the electrical action potential is a preferred mechanism for treating certain diseases, e.g., cardiac arrhythmias (Colatsky et al., Circulation 82:223 5, 1990). Membrane potential depolarization is a preferred mechanism for the treating of certain other diseases, such as those involving the immune system (Kaczorowski and Koo, Perspectives in Drug Discovery and Design, 2:233, 1994). In particular, blocking potassium channels has been shown to regulate a variety of biological processes including cardiac electrical activity (Lynch et al., FASEB J 6:2952, 1992; Sanguinetti, Hypertension 19:228, 1992; Deal et al., Physiol. Rev. 76:49, 1996), neurotransmission (Halliwell, “K+ Channels in the Central Nervous System” in Potassium Channels, Ed. N. S. Cook, pp348, 1990), and T cell activation (Chandy et al., J. Exp. Med. 160:369, 1984; Lin et al., J. Exp. Med. 177:637, 1993). These effects are mediated by specific subclasses or subtypes of potassium channels.
Potassium channels have been classified according to their biophysical and pharmacological characteristics. Salient among these are the voltage dependent potassium channels, such as Kv1. The Kv1 class of potassium channels is further subdivided depending on the molecular sequence of the channel, for example Kv1.1, Kv1.3, and Kv1.5. Functional voltage-gated K+ channels can exist as multimeric structures formed by the association of either identical or dissimilar subunits. This phenomena is thought to account-for the wide diversity of K+ channels. However, subunit compositions of native K+ channels and the physiologic role that particular channels play are, in most cases, still unclear.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and is likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M. “A Third Class Of Anti-Arrhythmic Action: Effects On Atrial And Ventricular Intracellular Potentials And Other Pharmacological Actions On Cardiac Muscle, of MJ 1999 and AH 3747” Br. J. Pharmacol 1970; 39:675-689 and Singh, B. N., Vaughan Williams E. M., “The Effect Of Amiodarone, A New Anti-Anginal Drug, On Cardiac Muscle”, Br J. Pharmacol 1970; 39:657-667.), but these are not selective Class III agents. Sotalol also possesses Class II effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone, also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited-by side effects (Nademanee, K. “The Amiodarone Odyssey”. J. Am. Coll. Cardiol. 1992; 20:1063-1065.) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter INa and ICa, respectively) or by reducing outward repolarizing potassium (K+) currents. The delayed rectifier (IK) K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (Ito) and inward rectifier (IK1) K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that IK consists of two pharmacologically and kinetically distinct K+ current subtypes, IKr (rapidly activating and deactivating) and IKs (slowly activating and deactivating) (Sanguinetti and Jurkiewicz, “Two Components Of Cardiac Delayed Rectifier K+ Current: Differential Sensitivity To Block By Class III Antiarrhythmic Agents,” J. Gen. Physiol. 1990, 96:195-215). Class III antiarrhythmic agents, including d-sotalol and dofetilide predominantly, if not exclusively, block IKr. Although, amiodarone is a blocker of IKs (Balser, J. R. Bennett, P. B., Hondeghem, L. M. and Roden, D. M. “Suppression Of Time-Dependent Outward Current In Guinea Pig Ventricular Myocytes: Actions Of Quinidine And Amiodarone.” Circ. Res. 1991, 69:519-529), it also blocks INa and ICa, affects thyroid function, is a nonspecific adrenergic blocker, and acts as an inhibitor of the enzyme phospholipase (Nademanee, K. “The Amiodarone Odyssey”. J. Am. Coll. Cardiol. 1992; 20:1063-1065). Therefore, its method of treating arrhythmia is uncertain.
Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging action potential duration (APD), prevents and/or terminates reentrant arrhythmias. Most selective Class III antiarrhythmic agents, such as d-sotalol and dofetilide predominantly, if not exclusively, block IKr, the rapidly activating component of IK found both in atria and ventricles in man.
Since these IKr blockers increase APD and refractoriness both in atria and ventricles without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de points has been observed when these compounds are utilized (Roden, D. M. “Current Status of Class III Antiarrhythmic Drug Therapy,” Am. J. Cardiol. 1993; 72:44B-49B).
The ultra-rapidly activating delayed rectifier K+ current (IKur) is believed to represent the native counterpart to a cloned potassium channel designated Kv1.5 and, while present in human atria, it appears to be absent in human ventricles. Furthermore, because of its rapidity of activation and limited slow inactivation, IKur is believed to contribute significantly to repolarization in human atria and thus is a candidate potassium channel target for the treatment of cardiac arrhythmias especially those occurring in the atria. (Wang et al., Circ. Res. 73:1061, 1993; Fedida et al., Circ. Res. 73:210, 1993; Wang et al., J. Phartnacol. Exp. Aer. 272:184, 1995; Amos et al., J. Physiol., 491:31, 1996). Consequently, a specific blocker of Ikur, that is a compound which blocks Kv1.5, would overcome the shortcoming of other compounds by prolonging refractoriness in human atria without prolonging ventricular refractoriness that underlie arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III drugs.
Natsugari et al. (EP 0481383) discloses the heterocyclic amine derivatives having an activity of inhibiting acyl-CoA: cholesterol acyltranferase, controlling in mammals, absorption of cholesterol from the intestinal tract and suppressing accumulation of cholesterol ester at the arterial wall thus being useful for prophylaxis and therapy of hypercholesterolemia, atherosclerosis and various diseases caused by them (e.g. ischemic heart diseases such as cardiac infarction and cerebral blood vessel disorders such as cerebral infarction, apoplexy, etc.).
Natsugari, et al. (EP 0585913) is directed to phenyl substituted heterocyclic compounds which are inhibitors of acylCoA: cholesterol transferase (ACAT) and antagonists of tachykinin receptors, and pharmaceutical compositions containing these compounds, process for preparing these compounds, and the use of these compounds for preparing medicaments for treating hypercholesterolemia and artherosclerosis, and for treating pain, disturbance of micturition and inflammation. Natsugari et al. (J. Med. Chem. 38:16; 1995; 3106-3120, “Novel Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine”) relates to a synthesis of 4-phenylisoquinolone derivatives and NK1 (substance P) antagonist activity of the compounds.
Castle et al. (WO 99/62891) discloses certain thiazolidinone and methathiazanone compounds that are useful as potassium channel inhibitors and for the treatment of cardiac arrhythmias and other diseases, conditions and disorders.
An object of the present invention is directed to the compounds that are useful as inhibitors of potassium channel function and are selective for atrial tissue avoiding side effects of affecting ventricular repolarization. The potassium channel inhibitors of the present invention may therefore be utilized for the treatment of diseases in which prolongation of cellular action potentials would be beneficial, such as cardiac arrhythmia, and particularly atrial arrhythmia.